Cited by 353Pancreatic and Hepatic Oncology ResearchBreast Cancer Treatment StudiesCholangiocarcinoma and Gallbladder Cancer Studies

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GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer

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O’Kane, Grainne M., Grünwald, Barbara T., Jang, Gun-Ho, Masoomian, Mehdi, Picardo, Sarah, Grant, Robert C., Denroche, Robert E., Zhang, Amy, Wang, Yifan, Miller, Jessica K., Lam, Bernard, Krzyzanowski, Paul M., Lungu, Ilinca M., Bartlett, John M.S., Peralta, Melanie, Vyas, Foram, Khokha, Rama, Biagi, James, Chadwick, Dianne, Ramotar, Stephanie, Hutchinson, Shawn, Dodd, Anna, Wilson, Julie M., Notta, Faiyaz, Zogopoulos, George, Gallinger, Steven, Knox, Jennifer J., Fischer, Sandra E.·2020·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-19-3724

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Abstract

Purpose: To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker. Experimental Design: Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) was explored. Results: Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (P = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (n = 22), the progression rate was 60% compared with 15% in classical PDAC (P = 0.0002). Median OS in the intention-to-treat population (n = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32–0.69; P = 0.0001). GATA6 expression by RNA-seq highly correlated with the classifier (P < 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (P = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell–inflamed gene expression signature. Conclusions: The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression. See related commentary by Collisson, p. 4715

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Authors: O’Kane, G. M., Grünwald, B. T., Jang, G.-H., Masoomian, M., Picardo, S., Grant, R. C., Denroche, R. E., Zhang, A., Wang, Y., Miller, J. K., Lam, B., Krzyzanowski, P. M., Lungu, I. M., Bartlett, J. M. S., Peralta, M., Vyas, F., Khokha, R., Biagi, J., Chadwick, D., Ramotar, S., Hutchinson, S., Dodd, A., Wilson, J. M., Notta, F., Zogopoulos, G., Gallinger, S., Knox, J. J., & Fischer, S. E.
Affiliations: 1Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Ontario Institute for Cancer Research (CA)
University Health Network (CA)
Research Institute of the McGill University Health Centre (CA)
Kingston General Hospital (CA)
ORCID: Grünwald, Barbara T.
Jang, Gun-Ho
Grant, Robert C.
Denroche, Robert E.
Zhang, Amy
Wang, Yifan
Miller, Jessica K.
Lam, Bernard
Krzyzanowski, Paul M.
Lungu, Ilinca M.
Bartlett, John M.S.
Peralta, Melanie
Vyas, Foram
Khokha, Rama
Biagi, James
Ramotar, Stephanie
Hutchinson, Shawn
Dodd, Anna
Wilson, Julie M.
Notta, Faiyaz
Zogopoulos, George
Knox, Jennifer J.
Fischer, Sandra E.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2020-03-10
Volume: 26
Issue: 18
Pages: 4901-4910
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-19-3724
OpenAlex: W3011562658
Semantic Scholar: d72ef3593540c2afcd56ffaaa1ecbdf174cca98b
Cited by: 352
References: 39
Citations by year: 2026: 54 · 2025: 58 · 2024: 58 · 2023: 60 · 2022: 48 · 2021: 56 · 2020: 16
FWCI: 16.25
Type: journal article
Language: en
Update notices: correction (2022-06-13)
Open access: green
www.research.ed.ac.uk
Licence: other-oa
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders: Princess Margaret Cancer Foundation (ALTF 116-2018, DEU 1199182 FLF-P)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
Keywords: GATA6, pancreatic ductal adenocarcinoma, basal-like subtype, classical subtype, cancer subtyping, chemoresistance, modified FOLFIRINOX, overall survival, prognostic factors, keratin 5, tumor hypoxia, COMPASS trial
MeSH terms: Irinotecan, Oxaliplatin, RNA-Seq, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Female, Fluorouracil, Humans, Male, Middle Aged, Pancreatic Neoplasms, Prognosis, Prospective Studies, Multicenter Studies as Topic, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, GATA6 Transcription Factor, Response Evaluation Criteria in Solid Tumors

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GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer

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